EP0676951B1 - Use of vitamin d glycosides for the treatment or prevention of osteoporosis - Google Patents
Use of vitamin d glycosides for the treatment or prevention of osteoporosis Download PDFInfo
- Publication number
- EP0676951B1 EP0676951B1 EP94904520A EP94904520A EP0676951B1 EP 0676951 B1 EP0676951 B1 EP 0676951B1 EP 94904520 A EP94904520 A EP 94904520A EP 94904520 A EP94904520 A EP 94904520A EP 0676951 B1 EP0676951 B1 EP 0676951B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- hydrogen
- vitamin
- osteoporosis
- glycosidic
- proviso
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 0 CCC1OC(C)(*=C)OC1C Chemical compound CCC1OC(C)(*=C)OC1C 0.000 description 3
- SIOHJAJKWCISDH-UHFFFAOYSA-N CC1OC(C)(N)OC1C Chemical compound CC1OC(C)(N)OC1C SIOHJAJKWCISDH-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/02—Nutrients, e.g. vitamins, minerals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the invention is in the field of Medical Chemistry.
- U.S. Patent No. 4,725,596 discloses methods for treating or preventing metabolic bone disease characterized by the loss of bone mass by administering at least one compound having the formulae (I) and (II): where R 1 , R 2 and R 3 are each selected from the group consisting of hydrogen, hydroxyl, lower alkyl, acyl and O-alkyl and R 3 is selected from the group consisting of hydrogen, hydroxyl, keto, lower alkyl, acyl and O-alkyl.
- U.S. Patent No. 4,410,515 discloses the following compounds having Formula (III) which are active in maintaining calcium and phosphorus metabolism and are useful for treating hypocalcemia in animals: wherein the double bond between positions C-22 and C-23 is single or double; R 2 is hydrogen, CH 3 or CH 2 CH 3 ; X is selected from the group consisting of hydrogen and -OR 1 , where R 1 is hydrogen or a straight or branched chain glycosidic residue containing 1-20 glycosidic units per residue; with the proviso that at least one of the R 1 is glycosidic residue.
- U.S. Patent No. 5,167,953 discloses a method for the treatment of osteoporosis using a composition
- a composition comprising a compound having the formula: wherein the bond between C-22 and C-23 is a single or a double bond;
- X is hydrogen, methyl or ethyl;
- R 1 is hydrogen or a straight or branched chain glycoside residue containing 1-20 glycosidic units per residue, or R 1 is an orthoester glycoside moiety of the formula: where A represents a glucofuranosyl or glucopyranosyl ring;
- R 2 is hydrogen, lower (C 1 -C 4 )alkyl, C 7 -C 10 aralkyl, or C 6 -C 10 aryl; and
- R 3 is hydrogen or a straight on branch chain glycosidic residue; and wherein said compound is present in an amount effective to provide vitamin D to an individual when exposed to UV radiation of greater than 315 nm which is insufficient to effect the
- the present invention relates to the use of a compound having the formula given below, in the manufacture of a pharmaceutical composition for treating or preventing osteoporosis in an animal having osteoporosis or susceptible to osteoporosis.
- the bond between C-22 and C-23 is a single or a double bond
- Y 2 is hydrogen, fluorine, methyl, ethyl or OR 1
- Z 2 is F, H or X 2
- U is hydrogen, -OH or -O-(C 2 -C 4 alkyl)-OH
- Q a is CF 3 or CH 2 X 2
- Q b is CF 3 or CH 3
- R is a double bond or an epoxy group
- X 1 and X 2 are selected from the group consisting of hydrogen and OR 1
- R 1 is hydrogen or a straight or branched chain glycosidic residue containing 1-20 glycosidic units per residue, or R 1 is an orthoester glycoside moiety of the formula: wherein A represents a glycofuranos
- the invention is related to the discovery that compounds having Formula (IV) are useful in treating and preventing osteoporosis: wherein the bond between C-22 and C-23 is a single or double bond; Y 2 is hydrogen, fluorine, methyl, ethyl or OR 1 ; Z 2 is F, H or X 2 ; U is hydrogen, -OH or -O-(C 2 -C 4 alkyl)-OH; Q a is CF 3 or CH 2 X 2 ; Q b is CF 3 or CH 3 ; R is a double bond or an epoxy group; X 1 and X 2 are selected from the group consisting of hydrogen, and OR 1 , R 1 is hydrogen or a straight or branched chain glycosidic residue containing 1-20 glycosidic units per residue, or R 1 is an orthoester glycoside moiety of the Formula (V): wherein A represents a glycofuranosyl or glycopyranosyl ring; R 2 is hydrogen, lower alkyl, aralkyl,
- Any animal which experiences osteoporosis and which may benefit from the vitamin D glycosides and orthoester glycosides of Formula IV may be treated according to the present invention.
- Preferred animals are of course humans, in particular, pre- or post menopausal women. When administered to a pre-menopausal woman, it is possible to prevent osteoporosis. When administered to a post-menopausal woman, it is possible to reverse the adverse consequences of osteoporosis mentioned above, and arrest the further deterioration of the bones.
- the vitamin D glycosides and orthoester glycosides of the present invention have the distinct advantage that they promote calcium absorption through the intestine without effecting calcium mobilization from the bones.
- the vitamin D glycosides and orthoester glycosides of Formula IV are uniquely suited for the treatment of osteoporosis.
- glycosidic units are meant glycopyranosyl or glycofuranosyl, as well as their amino sugar derivatives.
- the residues may be homopolymers, random or alternating or block copolymers thereof.
- R 4 is acetyl or propionyl; phenyl, nitrophenyl, halophenyl, lower alkyl substituted phenyl, lower alkoxy substituted phenyl, and the like or benzyl, lower alkoxy substituted benzyl and the like.
- the compounds of Formula (IV) When the compounds of Formula (IV) have a double bond at position C-22 and a methyl group at C-24, they are derivatives of vitamin D 2 , whereas if the bond at that position is single, and there is a lack of C 24 alkyl, they are derivatives of vitamin D 3 .
- the compounds useful in the practice of the invention contain at least one glycoside residue at positions 1, 3, 24, 25 or 26. They may contain, however, more than one and up to five glycoside residues simultaneously.
- glycosides of 1-hydroxyvitamins D 3 or D 2 are preferred; and 1,25-dihydroxyvitamins D 3 or D 2 , 1,24-dihydroxyvitamin D 3 , 5,6-epoxy derivatives of vitamin D and its metabolites, 2- ⁇ -(3-hydroxypropoxy)-1 alpha,25-dihydroxyvitamin D 3 , as well as the side chain fluoro derivatives of 1,25-(OH) 2 vitamin D and 1-(OH) vitamin D.
- 20- and 22-oxa vitamin D derivatives including 20-oxa-1 ⁇ (OH)D, 20-oxa-1 ⁇ ,25(OH) 2 D 3 , 22-oxa-1 ⁇ (OH)D 3 and22-oxa-1 ⁇ ,25(OH)D 3 as well as pseudo-1-alpha-hydroxyvitamin D derivatives such as dihydrotachysterol and 5,6-trans vitamin D 3 and their 25-hydroxy derivatives.
- calcipotriol having the formula: See Krayballe, K., Arch. Dermatol. 125 :1647 (1989).
- glycosides include vitamin D 3 , 3 ⁇ -( ⁇ -D-glucopyranoside); vitamin D 3 , 3 ⁇ -( ⁇ -D-fructofuranoside); vitamin D 3 , 3 ⁇ -(galactosyl); vitamin D 3 , 3 ⁇ -( ⁇ -maltoside); vitamin D 3 , 3 ⁇ -( ⁇ -lactoside); vitamin D 3 , 3 ⁇ -( ⁇ -trehaloside); vitamin D 3 , 3 ⁇ -raffinoside; vitamin D 3 , 3 ⁇ -gentiobioside; 1 ⁇ -hydroxyvitamin D 3 , 3 ⁇ -( ⁇ -D-glucopyranoside); 1 ⁇ -hydroxyvitamin D 3 , 3 ⁇ -( ⁇ -D-fructofuranoside); 1 ⁇ -hydroxyvitamin D 3 , 3 ⁇ -( ⁇ -cellobioside); 1 ⁇ -hydroxy-3 ⁇ -( ⁇ -maltosyl)vitamin D 3 ; 1 ⁇ -hydroxy-3 ⁇ -raffinosylvitamin D 3 ; 1 ⁇ -hydroxy-3 ⁇ --r
- 1 ⁇ ,24-dihydroxyvitamin D 3 3 ⁇ -( ⁇ -D-glucopyranoside); 1 ⁇ ,24-dihydroxyvitamin D 3 , 3 ⁇ -( ⁇ -D-fructofuranoside); 1 ⁇ -( ⁇ -D-glycopyranosyl)-24-hydroxyvitamin D 3 ; 1 ⁇ -( ⁇ -D-fructofuranosyl)-24-hydroxyvitamin D 3 ; 1 ⁇ -hydroxy-24( ⁇ -D-fructofuranosyl) vitamin D 3 ; 1 ⁇ -hydroxy-24-( ⁇ -glycopryanosyl)vitamin D 3 ; 1 ⁇ -hydroxyl, 24-( ⁇ -maltosyl)vitamin D 3 ; 1 ⁇ -hydroxy, 24-( ⁇ -lactosyl)vitamin D 3 ; 1 ⁇ -hydroxy, 24- ⁇ -trehalosylvitamin D 3 ; 1 ⁇ -hydroxy, 24-raffinosylvitamin D 3 ; and 1 ⁇ -hydroxy, 24-gentiobiosyl
- the preferred compounds of the invention are those wherein less than all of the multiple hydroxy groups are glycosylated, most preferably those were only one of the multiple hydroxy groups is glycosylated.
- the glycosides can comprise up to 20 glycosidic units. Preferred, however, are those having less than 10, most preferred, those having 3 or less than 3 glycosidic units. Specific examples are those containing 1 or 2 glycosidic units in the glycoside residue.
- glycopyranose or glycofuranose rings or amino derivatives thereof may be fully or partially acylated or completely deacylated.
- the completely or partially acylated glycosides are useful as defined intermediates for the synthesis of the deacylated materials.
- glycopyranosyl structures glucose, mannose, galactose, gulose, allose, altrose, idose, or talose.
- the preferred ones are those derived from fructose, arabinose or xylose.
- preferred diglycosides are sucrose, cellobiose, maltose, lactose, trehalose, gentiobiose, and melibiose.
- the preferred ones may be raffinose or gentianose.
- amino derivatives are N-acetyl-D-galactosamine, N-acetyl-D-glucosamine, N-acetyl-D-mannosamine, N-acetylneuraminic acid, D-glucosamine, lyxosylamine, D-galactosamine, and the like.
- the individual glycosidic rings may be bonded by 1-1, 1-2, 1-3, 1-4, 1-5 or 1-6 bonds, most preferably 1-2, 1-4 and 1-6.
- the linkages between individual glycosidic rings may be ⁇ or ⁇ .
- the configuration of the oxygen linkage of a hydroxy group, or glycosidic residue attached to the vitamin D 3 or D 2 molecule may be either ⁇ (out of the plane of the paper) or ⁇ (into the plane of the paper). It is preferred if the configuration of the 3-hydroxy or glycosidoxy group at C-3 be ⁇ , and that, independently or simultaneously the configuration of the hydroxy or glycosidoxy at C-1 be ⁇ .
- the starting vitamin D compounds are prepared or obtained according to methods which are well known to those of ordinary skill in the art.
- the 5,6-epoxy derivatives of vitamin D 3 are obtained as described in Jpn. Kokai Tokkyo Koho JP 58,216,178 [83,216,178], Dec. 15, 1983.
- the fluoro derivatives are made or obtained as described in Shiina, et al ., Arch. Biochem. Biophys. 220 :90 (1983).
- Methods for preparing the 20- and 22-oxa vitamin D derivatives are disclosed by Abe, J., et al., Vitamin D Molecular, Cellular and Clinical Endocrinology , p. 310-319, Walter de Gruyter & Co., Berlin (1988).
- U.S. Patent No. 4,719,205 to DeLuca et al. discloses methods for the preparation of 22,23-cis-unsaturated, 1-hydroxyvitamin D compounds.
- U.S. Patent No. 4,634,692 to Partidge et al. discloses methods for the preparation of 1,25-dihydroxy-24 (R or S)-fluorovitamin D.
- Japanese Patent Application, publication no. J55 111-460 discloses methods for the preparation of 24,24-difluoro-25-hydroxyvitamin D 3 .
- the water soluble glycosidic derivatives of the aforementioned compounds may be obtained according to Holick, U.S. Patent 4,410,515.
- the vitamin D glycosyl orthoester compounds may be obtained according to U.S. Patent 4,521,410.
- the compounds of the invention can be administered in any appropriate pharmaceutically acceptable carrier for oral, parenteral, or topical administration. They can be administered by any means that treats or prevents osteoporosis in animals, especially humans.
- the dosage administered will be dependent upon the age, health and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment and the nature of the effect desired.
- systemic daily dosage of 1 ⁇ -( ⁇ -glucopyranosyl)-25-hydroxyvitamin D 3 will be from 0.001 micrograms/kg to 100 micrograms/kg preferably 0.01 to 1.0 micrograms per kg of body weight. Normally, from 0.1 to 100 micrograms/kg per day of the glycoside or orthoester glycoside, in one or more dosages per day is effective to obtain the desired results.
- One of ordinary skill in the art can determine the optimal dosages and concentrations of other active vitamin D glycoside and orthoester glycoside compounds with only routine experimentation.
- the compounds can be employed in dosage forms such as tablets, capsules, powder packets, or liquid solutions, suspensions or elixirs for oral administration, sterile liquid for formulations such as solutions or suspensions for parenteral use.
- the compounds may be administered transdermally via a patch or ointment and the like.
- the active ingredient will ordinarily be present in an amount of at least 10 -6 % by weight based upon the total weight of the composition, and not more than 90% by weight.
- An inert pharmaceutically acceptable carrier is preferably used.
- Such carriers include 95% ethanol, vegetable oils, propylene glycols, saline buffers, etc.
- a control group received 0.1 ml of propylene glycol. The animals were dosed for five days.
- the blood calcium levels are normal.
- 1,25(OH) 2 D 3 causes an undesired increase in blood calcium levels. Therefore, the vitamin D glycosides and orthoester glycosides are uniquely effective for the treatment of osteoporosis by increasing in a physiologic manner the efficiency of intestinal calcium absorption and bone calcium mobilization and increasing circulating concentrations of 1,25(OH) 2 D 3 , without the side effects associated with the administration of 1,25(OH) 2 D 3 .
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Molecular Biology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nutrition Science (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US99795192A | 1992-12-29 | 1992-12-29 | |
US997951 | 1992-12-29 | ||
PCT/US1993/012506 WO1994014411A1 (en) | 1992-12-29 | 1993-12-22 | Use of vitamin d glycosides for the treatment or prevention of osteoporosis |
Publications (3)
Publication Number | Publication Date |
---|---|
EP0676951A1 EP0676951A1 (en) | 1995-10-18 |
EP0676951A4 EP0676951A4 (en) | 1997-08-06 |
EP0676951B1 true EP0676951B1 (en) | 2002-04-17 |
Family
ID=25544594
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP94904520A Expired - Lifetime EP0676951B1 (en) | 1992-12-29 | 1993-12-22 | Use of vitamin d glycosides for the treatment or prevention of osteoporosis |
Country Status (9)
Country | Link |
---|---|
US (1) | US5508392A (ja) |
EP (1) | EP0676951B1 (ja) |
JP (1) | JPH08505147A (ja) |
AU (1) | AU5853894A (ja) |
CA (1) | CA2152163A1 (ja) |
DE (1) | DE69331833T2 (ja) |
DK (1) | DK0676951T3 (ja) |
ES (1) | ES2173911T3 (ja) |
WO (1) | WO1994014411A1 (ja) |
Families Citing this family (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
HUP0200871A3 (en) | 1999-05-04 | 2004-04-28 | Strakan Int Ltd | Androgen glycosides and androgenic activity thereof |
WO2001027129A1 (en) * | 1999-10-08 | 2001-04-19 | Strakan Limited | Glycosides and orthoester glycosides of raloxifene and analogues and the use thereof |
WO2001027127A1 (en) * | 1999-10-08 | 2001-04-19 | Strakan Group Plc | Tamoxifen and tamoxifen analogue glycosides and uses thereof |
AU2003217791A1 (en) | 2002-02-28 | 2003-09-16 | A And D Bioscience, Inc. | Glycuronamides, glycosides and orthoester glycosides of fluoxetine, analogs and uses thereof |
WO2003079980A2 (en) * | 2002-03-19 | 2003-10-02 | A & D Bioscience, Inc. | Caboxylic acid glycuronides, glycosamides and glycosides of quinolones, penicillins, analogs, and uses thereof |
US20050255038A1 (en) * | 2002-04-12 | 2005-11-17 | A And D Bioscience, Inc. | Conjugates comprising cancer cell specific ligands, a sugar and diagnostic agents and uses thereof |
US20050153928A1 (en) * | 2002-05-07 | 2005-07-14 | Holick Michael F. | Conjugates comprising a central nervous system-active drug linked to glucuronic acid or glucosamine through an amide bond and uses thereof |
US20050215487A1 (en) * | 2002-06-27 | 2005-09-29 | Holick Michael F | Conjugates comprising an nsaid and a sugar and uses thereof |
BRPI0822540B1 (pt) * | 2008-04-21 | 2023-05-16 | Herbonis Ag | Método para a preparação e purificação de um extrato de planta enriquecido de solanum glaucophyllum tendo um teor enriquecido de glicosídeos de 1,25-di-hidroxivitamina d3 e glicosídeos de quercetina |
KR101991692B1 (ko) | 2009-01-27 | 2019-06-21 | 베르그 엘엘씨 | 화학요법과 연관된 부작용을 경감시키기 위한 비타민 d3 및 이의 유사물 |
EA201270226A1 (ru) | 2009-08-14 | 2012-09-28 | БЕРГ БАЙОСИСТЕМЗ, ЭлЭлСи | Витамин d3 и его аналогии для лечения алопеции |
NZ600003A (en) * | 2009-10-20 | 2013-08-30 | Herbonis Ag | Composition comprising solanum glaucophyllum for preventing and/or treating hypocalcaemia and for stabilizing blood calcium levels |
EP3003497B1 (en) | 2013-05-29 | 2024-02-14 | BPGbio, Inc. | Preventing or mitigating chemotherapy induced alopecia using vitamin d |
Family Cites Families (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4410515A (en) * | 1981-04-01 | 1983-10-18 | Massachusetts General Hospital | Vitamin D glycosides and a method of use |
US4729999A (en) * | 1984-10-12 | 1988-03-08 | Bcm Technologies | Antiestrogen therapy for symptoms of estrogen deficiency |
US4772467A (en) * | 1985-02-19 | 1988-09-20 | Board Of Regents, U T Systems | Osteoporosis inhibition by dietary calcium supplementation |
US4740364A (en) * | 1985-09-27 | 1988-04-26 | Eastern Virginia Medical Authority | Predicting predisposition to osteoporosis |
US5104864A (en) * | 1988-08-02 | 1992-04-14 | Bone Care International, Inc. | Method for treating and preventing loss of bone mass |
CA2010982C (en) * | 1989-02-28 | 2000-06-13 | Toshio Matsumoto | Osteogenesis promotion with use of vitamin d derivatives |
JPH05503922A (ja) * | 1989-10-04 | 1993-06-24 | トラスティーズ・オブ・ボストン・ユニバーシティー | 創傷及び潰瘍の治癒の促進並びに歯周病の処置方法 |
US5116828A (en) * | 1989-10-26 | 1992-05-26 | Nippon Zoki Pharmaceutical Co., Ltd. | Pharmaceutical composition for treatment of osteoporosis |
US5013728A (en) * | 1990-05-04 | 1991-05-07 | Colgate - Palmolive Company | Composition for treating osteoporosis and hormonal imbalance |
US5167953A (en) * | 1990-06-21 | 1992-12-01 | Trustees Of Boston University | Compositions comprising tachysteral and the use thereof to provide vitamin D |
US5194248A (en) * | 1990-06-21 | 1993-03-16 | Trustees Of Boston University | Compositions comprising vitamin D analog precursors and the use thereof |
-
1993
- 1993-12-22 JP JP6515425A patent/JPH08505147A/ja active Pending
- 1993-12-22 EP EP94904520A patent/EP0676951B1/en not_active Expired - Lifetime
- 1993-12-22 WO PCT/US1993/012506 patent/WO1994014411A1/en active IP Right Grant
- 1993-12-22 AU AU58538/94A patent/AU5853894A/en not_active Abandoned
- 1993-12-22 ES ES94904520T patent/ES2173911T3/es not_active Expired - Lifetime
- 1993-12-22 DE DE69331833T patent/DE69331833T2/de not_active Expired - Fee Related
- 1993-12-22 CA CA002152163A patent/CA2152163A1/en not_active Abandoned
- 1993-12-22 DK DK94904520T patent/DK0676951T3/da active
-
1994
- 1994-04-20 US US08/230,867 patent/US5508392A/en not_active Expired - Fee Related
Also Published As
Publication number | Publication date |
---|---|
DE69331833D1 (de) | 2002-05-23 |
EP0676951A4 (en) | 1997-08-06 |
JPH08505147A (ja) | 1996-06-04 |
DE69331833T2 (de) | 2002-11-14 |
EP0676951A1 (en) | 1995-10-18 |
WO1994014411A1 (en) | 1994-07-07 |
CA2152163A1 (en) | 1994-07-07 |
ES2173911T3 (es) | 2002-11-01 |
US5508392A (en) | 1996-04-16 |
DK0676951T3 (da) | 2002-06-03 |
AU5853894A (en) | 1994-07-19 |
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